Increased GABA Contributes to Enhanced Control over Motor Excitability in Tourette Syndrome

Abstract

SummaryTourette syndrome (TS) is a developmental neurological disorder characterized by vocal and motor tics [1] and associated with cortical-striatal-thalamic-cortical circuit dysfunction [2, 3], hyperexcitability within cortical motor areas [4], and altered intracortical inhibition [4–7]. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence in many individuals [1], who exhibit enhanced control over their volitional movements [8–11]. Importantly, control over motor outputs appears to be brought about by a reduction in the gain of motor excitability [6, 7, 12, 13]. Here we present a neurochemical basis for a localized gain control mechanism. We used ultra-high-field (7 T) magnetic resonance spectroscopy to investigate in vivo concentrations of γ-aminobutyric acid (GABA) within primary and secondary motor areas of individuals with TS. We demonstrate that GABA concentrations within the supplementary motor area (SMA)—a region strongly associated with the genesis of motor tics in TS [14]—are paradoxically elevated in individuals with TS and inversely related to fMRI blood oxygen level-dependent activation. By contrast, GABA concentrations in control sites do not differ from those of a matched control group. Importantly, we also show that GABA concentrations within the SMA are inversely correlated with cortical excitability in primary motor cortex and are predicted by motor tic severity and white-matter microstructure (FA) within a region of the corpus callosum that projects to the SMA within each hemisphere. Based upon these findings, we propose that extrasynaptic GABA contributes to a form of control, based upon localized tonic inhibition within the SMA, that may lead to the suppression of tics.

Inhibition, Disinhibition, and the Control of Action in Tourette Syndrome

“…Studies that have investigated TMS-induced increases in motor cortical excitability in TS have repeatedly shown that the gain in motor cortical excitability is significantly reduced in individuals with TS [54,56] (Figure 1A). Similarly, studies that have used TMS to investigate alterations in the gain in motor cortical excitability ahead of volitional movements have reported that the gain in motor cortical excitability is significantly reduced in individuals with TS [55,57,58] (Figure 1B), and that reduced motor gain functions are associated with increased tic severity [58] (Figure 1C).…”

“…Instead, to the extent that apparently compensatory alterations in brain structure and function have been identified in TS, these may in fact operate to decrease or limit neural communication with cortical motor areas and thus reduce tics [35,54]. It has been proposed that a secondary consequence of TS is that enhanced control over volitional movements, and the suppression of tics, may arise as a result of increased 'tonic' inhibition (Box 1) in which localized suppression of cortical excitability may be achieved through an alteration in the inhibitory tone of motor areas [4,35,40,54,55].…”

“…motor excitability. Specifically, in vivo concentrations of GABA were measured within primary and secondary motor areas of adolescents with TS relative to an age-and gender-matched control group [54]. GABA concentrations were collected from three regions-of-interest (ROIs): the hand area of the left primary sensorimotor cortex (M1), bilaterally from within the SMA, and from a control site centered upon the primary visual cortex (V1).…”

Gilles de la Tourette syndrome

“…In the cortex, a deficiency of inhibitory interneurons is suggested by a reduction of short-interval intracortical inhibition measured by transcranial magnetic stimulation and a reduction of GABA measured by 3T MRS in the primary sensorimotor cortex 25 . In contrast, 7T-MRS has shown elevated concentrations of GABA within the supplementary motor area 26 . In rodent and primate models, disruption of striatal and cortical…”

“…GABAergic connectivity by local injections of GABAA antagonists has produced tic-like behaviors 21,26,27 . Other supporting evidence for GABA involvement includes the beneficial therapeutic effect of benzodiazepines and an association between GABA-related genes and tic severity 28 .…”